EP1123931B1 - Tricylic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases - Google Patents

Tricylic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases Download PDF

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EP1123931B1
EP1123931B1 EP01109408A EP01109408A EP1123931B1 EP 1123931 B1 EP1123931 B1 EP 1123931B1 EP 01109408 A EP01109408 A EP 01109408A EP 01109408 A EP01109408 A EP 01109408A EP 1123931 B1 EP1123931 B1 EP 1123931B1
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formula
compound
benzo
compounds
dihydro
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EP1123931A1 (en
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Robert W. Bishop
Alan K. Mallams
Joanne M. Petrin
Ronald J. Doll
George F. Njoroge
John J. Piwinski
Stacy W. Remiszewski
Ronald L. Wolin
Arthur G. Taveras
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Merck Sharp and Dohme Corp
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Schering Corp
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
  • Tricyclic compounds useful in the methods of this invention are described in: (1) U.S. 5,151,423; (2) U.S. 4,826,853; (3) U.S. 5,089,496; (4) WO 88/03138 published on May 5, 1988 (PCT/US87/02777); and (5) U.S. 5,104,876; the disclosures of each being incorporated herein by reference thereto. Those compounds within the scope of this invention which are not described in these documents are described herein.
  • the reaction usually proceeds overnight to completion, i.e., the reaction usually proceeds for about 16 hours.
  • the reaction can be conducted within a temperature of 0°C to about 25°C during a time period of about 10 to about 24 hours.
  • Preferably the reaction is initially conducted at 0°C and the temperature is allowed to warm up to 25°C.
  • the reaction produces the 3-nitro compound:
  • This invention also provides a process for producing compounds of the formula (1.0j) which are useful as intermediates for preparing compounds of Formula (1.0): by reacting one molar equivalent a compound of formula: with one molar equivalent of a nitrating reagent, said nitrating reagent being preformed (i.e., prepared first) by mixing, at cold temperature (e.g., at 0°C) equimolar amounts of tetrabutyl ammonium nitrate with trifluoroacetic anhydride; the reaction of the nitrating reagent with the compound of Formula 1.0k taking place in a suitable aprotic solvent (e.g., methylene chloride, chloroform, toluene or tetrahydrofuran); said reaction with said nitrating reagent being conducted at a temperature and for a period of time sufficient to allow the reaction to proceed at a reasonable rate to produce the desired final 3-nitro compound of Formula 1.0j--i.e.
  • Compound 415.00 may be prepared from the N-alkyl compound shown as Formula 420.00 below, in the manner disclosed in U.S. Patents 4,282,233 and 4,335,036.
  • the Grignard intermediate 430.00 is formed by the reaction of the cyano compound 435.00 with an appropriate Grignard reagent 440.00 prepared from 1-alkyl-4halopiperidine.
  • the reaction is generally performed in an inert solvent, such as ether, toluene, or tetrahydrofuran, under general Grignard conditions e.g., temperature of from about 0°C to about 75°C.
  • inert solvent such as ether, toluene, or tetrahydrofuran
  • other organometallic derivatives of the 1alkyl-4-halo piperidine can be employed.
  • the compound of Formula 450.00a may be formed by hydrolysis of the corresponding nitrile wherein the appropriate cyanomethyl pyridine, such as 2-cyano-3-pyridine, is reacted with a tertiary butyl compound in acid, such as concentrated sulfuric acid or concentrated sulfuric acid in glacial acetic acid.
  • a tertiary butyl compound in acid such as concentrated sulfuric acid or concentrated sulfuric acid in glacial acetic acid.
  • Suitable tertiary butyl compounds include, but are not limited to, t-butyl alcohol, t-butyl chloride, t-butyl bromide, t-butyl iodide, isobutylene or any other compound which under hydrolytic conditions forms t-butyl carboxamides with cyano compounds.
  • the temperature of the reaction will vary depending upon the reactants, but generally the reaction is conducted in the range of from about 50°C to about 100°C with t-butyl alcohol.
  • the reaction
  • An alternative process for the formation of compounds of Formula 400.00a may involve direct cyclization of Compound 455.00 as shown below.
  • the azaketone N-oxide of Formula 470.00a can then be reacted with a chlorinating agent such as SO 2 Cl 2 or SOCl 2 to form a compound of Formula 470.00b.
  • a chlorinating agent such as SO 2 Cl 2 or SOCl 2
  • this reaction results in monosubstitution of Cl in the ortho or para-position relative to the N atom of the ring.
  • N-oxide of Formula 415.00 can be treated with POCI 3 to form a compound of Formula 415.01. Typically, this reaction results in monosubstitution of Cl in the ortho or para position relative to the N atom of the ring.
  • Tetrabutyl ammonium nitrate(4.98g, 16.3 mmol) was dissolved in dichloromethane(20 mL) and trifluoroacetic anhydride(3.12g,14.9 mmol, 2.1 mL) was then added. The solution was cooled to 0°C and then added (by cannulation) to a solution of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylic aid ethyl ester (5.69g, 14.9 mmol) in methylene chloride (35 mL) also cooled to 0°C.
  • reaction mixture was stirred at 0°C for 3h and then allowed to go to room temperature (25°C) overnight.
  • the reaction mixture was then extracted with saturated sodium bicarbonate (60 mL) dried over magnesium sulfate and concentrated to give a semi-solid material that was chromatographed on silica gel eluting first with 10% and then 20% ethyl acetate -hexane. Removal of the organic solvents gave the title compound in 44% yield as a light yellow solid.
  • MP 90.4-91.0°C, MH + 428.
  • reaction mixture was concentrated and chromatographed on a silica gel column eluting with 3% methanol saturated with ammonia in methylene chloride to give an off white borate salt solid (0.14g, 61% yield, MH + 446).
  • Example 255 To the title compound from Example 255 (0.18 grams) dissolved in anhydrous tetrahydrofuran (10 mL) was added 30% aqueous hydrogen peroxide (3 mL) and the resulting solution was stirred for 12 hours at 73°C. The solution was concentrated in vacuo , diluted with dichloromethane, and washed with water. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound after preparative plate chromatography (silica gel) using 3% methanol-dichloromethane (0.04 grams, 26%, MH + 492).
  • Example 250 A mixture of the title compound from Example 250 (0.24 grams), 5-mercapto-1-methyltetrazole sodium salt (0.6 grams) and anhydrous dimethylformamide (10 mL) was stirred while being irradiated with a 200 W lamp for 10 days. Isolation and purification as in Example 257 provided the title compound (0.2 grams, 68%, MH + 544).
  • Example 262 To a solution of the title compound form Example 262 (0.86 grams) and glacial acetic acid (20 mL) was added zinc dust (0.5 grams). After stirring at 25°C for 1.5 hours, the mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 5-10% methanol-dichloromethane saturated with ammonium hydroxide to give the title compound (Yield 0.47 grams, 69%, MH+448).
  • Example 266 The title compound from Preparative Example 34C above was treated as descibed in Example 266, using 4-pyridylacetic acid in place of 3-pyridylacetic acid, to give the title compound (M + 430).
  • Example 266 The title compound from Preparative Example 36C was treated as descibed in Example 266 to give the title compound (mp 100.1 - 103.4°C).
  • Example 279 The procedure of Example 279 was followed with the exception that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid to give the title compound (MH + 444).
  • Example 280 The procedure of Example 280 was followed with the exception that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid to give the title compound (MH + 446).
  • Example 283 The procedure of Example 283 was followed with the exception that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid to give the title compound (M + 444).
  • Example 284 The procedure of Example 284 was followed with the exception that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid to give the title compound (MH + 446).
  • Example 290 By essentially the same procedure as in Example 1, but using either (R)-(+)- ⁇ -methoxy- ⁇ -(trifluromethyl)-phenylacetic acid (Example 290), (S)-(-)- ⁇ -methoxy- ⁇ -(trifluromethyl)-phenylacetic acid (Example 287), or ⁇ , ⁇ -dimethylphenylacetic acid (Example 289), the compounds of Example 290, 287 and 289 were obtained.
  • the structures for these compounds are in Table 7. Data for these compounds are: compound of Example 290, white solid MH+ 527; compound of Example 287, white solid MH+ 527; and compound of Example 289, white solid M+ 457.
  • Example 183 By essentially the same procedure as in Example 183, and using either 4-, 3-, or 2-ethoxycarbonylaminopyridine and either 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine or 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (product of Example 233A), the compounds of Examples 291, 292, 294, 313 and 314 were obtained.
  • the structures for the compounds of Examples 291, 292, and 294 are given in Table 7.
  • the structures for the compounds of Examples 313 and 314 are given in Table 10.
  • Example 291 was a yellow solid (MH + 431)
  • the compound of Example 292 was an off white solid (MH + 431)
  • the compound of Example 294 was an off white solid (MH + 431)
  • the compound of Example 313 was a white solid (MH + 433)
  • the compound of Example 314 was a white solid (MH + 433).
  • Example 180 By essentially the same procedure as set forth in Example 180, but using 4-(8,9-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]-cyclohepta[1,2-b]pyridine (from Preparative Example 1H) instead of 4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine, and 3-pyridylacetic acid instead of 4-pyridylacetic acid, the title compound was obtained as white solid MH+ 464.
  • Example 312 By essentially the same procedure as in Example 182, with the exception that 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is used instead of 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, the compound of Example 312 was obtained as a white solid (MH + 432). The structure for this compound is given in Table 10.
  • Example 352 is a white amorphous solid, yield 65%, Mass Spec MH + 555.
  • the compound of Example 353 is a white amorphous solid, yield 59%, Mass Spec MH + 539.
  • Ras-CVLS cysteine-valine-laucine-serine
  • Ras-CVLL cystein-valine-leucine-leucine
  • the cDNAs encoding these proteins were constructed so that the proteins contain an amino-terminal extension of 6 histidine residues. Both proteins were expressed in Escherichia coli and purified using metal chelate affinity chromatography.
  • the radiolabelled isoprenyl pyrophosphate substrates, [ 3 H]famesyl pyrophosphate and [ 3 H]geranylgeranyl pyrophosphate, were purchased from DuPont/New England Nuclear.
  • the reaction mixture contained 40 mM Hepes, pH 7.5; 20 mM magnesium chloride; 5 mM dithiothreitol; 0.25 ⁇ M [ 3 H]farnesyl pyrophosphate; 10 ⁇ l Q-Sepharose-purified farnesyl protein transferase; the indicated concentration of tricyclic compound or dimethylsulfoxide (DMSO) vehicle control (5% DMSO final); and 5 ⁇ M Ras-CVLS in a total volume of 100 ⁇ l.
  • DMSO dimethylsulfoxide
  • the reaction was allowed to proceed for 30 minutes at room temperature and then stopped with 0.5 ml of 4% sodium dodecyl sulfate (SDS) followed by 0.5 ml of cold 30% trichloracetic acid (TCA).
  • SDS sodium dodecyl sulfate
  • TCA cold 30% trichloracetic acid
  • Samples were allowed to sit on ice for 45 minutes and precipitated Ras protein was then collected on GF/C filter paper mats using a Brandel cell harvester. Filter mats were washed once with 6% TCA, 2% SDS and radioactivity was measured in a Wallac 1204 Betaplate BS liquid scintillation counter. Percent inhibition was calculated relative to the DMSO vehicle control.
  • the geranylgeranyl protein transferase I assay was essentially identical to the farnesyl protein transferase assay described above, with two exceptions: [ 3 H]geranylgeranylpyrophosphate replaced farnesyl pyrophosphate as the isoprenoid donor and Ras-CVLL was the protein acceptor. This is similar to the assay reported by Casey et al (Casey, P.J., et al., (1991), Enzymatic modification of proteins with a geranylgeranyl isoprenoid, Proc. Natl. Acad. Sci, USA 88 : 8631-8635, the' disclosure of which is incorporated herein by reference thereto).
  • COS monkey kidney cells were transfected by electroporation with the plasmid pSV-SPORT (Gibco/BRL) containing a cDNA insert encoding either Ras-CVLS or Ras-CVLL, leading to transient overexpression of a Ras substrate for either farnesyl protein transferase or geranylgeranyl protein transferase I, respectively (see above).
  • cells were plated into 6-well tissue culture dishes containing 1.5 ml of Dulbecco's-modified Eagle's media (GIBCO, Inc.) supplemented with 10% fetal calf serum and the appropriate farnesyl protein transferase inhibitors. After 24 hours, media was removed and fresh media containing the appropriate drugs was re-added.
  • Dulbecco's-modified Eagle's media GEBCO, Inc.
  • Cellular protein was precipitated by addition of ice-cold trichloroacetic acid and redissolved in 100 ⁇ l of SDS-electrophoresis sample buffer. Samples (5-10 ⁇ l) were loaded onto 14% polyacrylamide minigels (Novex, Inc.) and electrophoresed until the tracking dye neared the bottom of the gel. Proteins resolved on the gels were electroblotted onto nitrocellulose membranes for immunodetection.
  • Membranes were blocked by incubation overnight at 4°C in PBS containing 2.5% dried milk and 0.5% Tween-20 and then incubated with a Ras-specific monoclonal antibody, Y13-259 (Furth, M.E., et al., (1982), Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcome virus and of the cellular ras gene family, J. Virol. 43 : 294-304), in PBS containing 1% fetal calf serum for one hour at room temperature.
  • a Ras-specific monoclonal antibody Y13-259
  • Normal human HEPM fibroblasts were planted in 3.5 cm dishes at a density of 5 x 10 4 cells/dish in 2 ml growth medium, and incubated for 3-5d to achieve confluence.
  • Medium was aspirated from each dish and the indicator tumor cells, T24-BAG4 human bladder carcinoma cells expressing an activated H-ras gene, were planted on top of the fibroblast monolayer at a density of 2 x 10 3 cells/dish in 2 ml growth medium, and allowed to attach overnight.
  • Compound-induced colony inhibition was assayed by addition of serial dilutions of compound directly to the growth medium 24 h after tumor cell planting, and incubating cells for an additional 14 d to allow colony formation.
  • Both IC 50 values were obtained by determining the density of tumor cells and mat cells by visual inspection and enumeration of cells per colony and the number of colonies under the microscope.
  • the therapeutic index of the compound was quantitatively expressed as the ratio of mIC 50 /tIC 50 , with values greater than one indicative of tumor target specificity.
  • EXAMPLE FPT IC 50 ( ⁇ M) EXAMPLE FPT IC 50 ( ⁇ M) EXAMPLE FPT IC 50 ( ⁇ M) 229* 0.01-10 231* 10-100 232* 0.01-10 (5.104) (5.106) (5.107) 236* 0.01-10 237* 10-100 238* 10-100 (5.111) (5.112) (5.113) 239* 0.01-10 240* 0.01-10 246* 0.01-10 (5.114) (5.115) (5.121) 247* 0.01-10 248* 0.01-10 248* 0.01-10 (5.122) (5.124) (5.123) 249* 0.01-10 250* 0.01-10 256* 0.01-10 (5.125) (5.126) (5.132) 257* 0.01-10 258* 10-100 259* 0.01-10 (5.133) (5.134) (5.135) 260* 0.01-10 266* 0.01-10 269* 0.01-10 (5.136) (5.138) (5.
  • EXAMPLE FPT IC 50 ( ⁇ M) EXAMPLE FPT IC 50 ( ⁇ M) EXAMPLE FPT IC 50 ( ⁇ M) 187 0.01-10 187 0.01-10 188 0.01-10 (6.7) (6.8) (6.9) 189* 0.01-10 190* 0.01-10 191* 0.01-10 (5.62) (5.63) (5.64) 192* 0.01-10 194* 0.01-10 195* 0.01-10 (5.65) (5.67) (5.68) 196* 0.01-10 197* 0.01-10 198* 0.01-10 (5.69) (5.70) (5.71) 199* 10-100 199* 10-100 200* 0.01-10 (5.72A) (5.72B) (5.73) 201* 0.01-10 202* 10-100 203* 10-100 (5.74) (5.75) (5.76) 205* 0.01-10 206* 0.01-10 207* 10-100 (5.78) (5.79) (5.80) 208* 0.01-10 209* 0.01-10 210* 0.01
  • Example 180* compound 5.47, 0.01-10 ⁇ M
  • Example 181* compound 5.48, 0.01-10 ⁇ M
  • Example 182 compound 6.4, 0.01-10 ⁇ M
  • Example 183 compound 6.5, 0.01-10 ⁇ M.
  • Example 157* is: INHIBITION OF TUMOR CELL GROWTH MAT ASSAY
  • Example Tumor IC 50 ( ⁇ M) Normal IC 50 ( ⁇ M) Example Tumor IC 50 ( ⁇ M) Normal IC 50 ( ⁇ M) 75* 2.5 >50.0 ---- ---- ---- 1* 3.1 25.0 82* 3.1 40.0 5* 6.3 >50.0 89* 6.3 >25.0 127* 6.3 >50.0 45* 6.3 >50.0 88* 8.0 >50.0 6* 12.5 50.0 49* 12.5 >50.0 47* 12.5 >50.0 48* 12.5 25.0 79* 12.5 >50.0 158 (5.36)* 12.5 18.0 2* 25.0 >50.0 10* 25.0 >50.0 128* 25.0 >50.0 44* 25.0 25.0 164 (5.30)* 25.0 >50.0 43* 25.0 50.0 165 (5.34)* 2
  • the data demonstrate that compounds of the invention are poorer inhibitors of geranylgeranyl protein transferase (GGPT) assayed using Ras-CVLL as isoprenoid acceptor.
  • the compounds of the invention are inactive or weakly active as geranylgeranyl transferase inhibitors at 20 ⁇ g/mL.
  • the compound of Example 1 inhibits GGPT 24% at 46 ⁇ M and is at least 184-fold selective for FPT inhibition.
  • the compound of Example 2 for example, inhibits GGPT 25% at 46 ⁇ M and is at least 98-fold selective for FPT inhibition.
  • the compound of Example 3 inhibits GPPT 3% at 39 ⁇ M and is at least 59-fold selective for FPT. This selectivity is important for the therapeutic potential of the compounds used in the methods of this invention, and increases the potential that the compounds will have selective growth inhibitory properties against Ras-transformed cells.
  • Example 1 inhibited the morphological changes induced by Ras-CVLS in a dose-dependent manner over the concentration range of 2 to 20 ⁇ g/mL.
  • the compound of Example 1 had little effect at 0.2 or 0.5 ⁇ g/mL.
  • 20 ⁇ g/mL of the compound of Example 1 did not prevent the morphological changes induced by Ras-CVLL.
  • Tricyclic farnesyl protein transferase inhibitors of this invention also inhibited the growth of Ras-transformed tumor cells in the Mat assay without displaying cytotoxic activity against the normal monolayer.
  • Tumor cells (5 x 10 5 to 8 x 10 6 of M27 (mouse Lewis lung carcinoma), A431(human epidermal carcinoma) or SW620 (human colon adenocarcinoma [lymph node metastasis]) are innoculated subcutaneously into the flank of 5-6 week old athymic nu/nu female mice.
  • C-f-1 mouse fibroblast transformed with c-fos oncogene
  • 2 mm 3 tumor fragments are transplanted subcutaneously into the flank of 5-6 week old athymic nu/nu female mice.
  • Tumor bearing animals are selected and randomized when the tumors are established. Animals are treated with vehicle (beta cyclodextran for i.p.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements, of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

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EP01109408A 1993-10-15 1994-10-12 Tricylic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases Expired - Lifetime EP1123931B1 (en)

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